3PHARMACOGENETICS HUNDREDS OR PROTEINS PARTICIPATE IN DRUG DISPOSITION MOST, IF NOT ALL, DISPLAY GENETIC POLYMORPHISMCRITICAL INTER-PATIENT VARIABILITY OCCURS WHEN DRUG LEVELS ARE TOO HIGH/LOW AT SITES OF ACTIONHISTORICALLY, THIS HAS BEEN ATTRIBUTED TO A FEW ENZYMES
4PHARMACOKINETICS - ++ +++ + PROCESS ENZYMES TRANSPORTERS ABSORPTION DISTRIBUTION+++METABOLISM+EXCRETION
5ROUTINE PHARMACOGENETICS CYP2D6 AND ANTIDEPRESSANTSCYP2C9 AND WARFARINTPMT AND AZATHIOPRINE/6-MP
8TRANSPORTERS30 years ago, drugs seen as subject only to passive diffusion from one compartment to anotherpH, pKa (Henderson-Hasselbach equation) and MW (Fick’s Law of diffusion) were the guiding principlesExceptions were amino acid absorption and renal excretion of a few drugs
15SLC AND ABC TRANSPORTERS SLC transporters41 families46 sub-families316 membersMultiple cellular locationsImport, export, exchangeWide range of endogenous and exogenous compoundsSLCO transporters6 families10 sub-families11 membersWide range of endogenous and exogenous anionic compoundsABC transporters1 family6 sub-families48 membersPlasma membraneExportWide range of endogenous and exogenous compoundsTOTAL NUMBER OF TRANSPORTERS375 members
19POLYMORPHISM OF TRANSPORTER FUNCTION GENETRANSPORTERDRUGSEFFECTS OF SINGLE NUCLEOTIDE POLYMORPHISMSREF.SLC29A1ENT1Nucleoside analoguesHaplotypes do not alter uptake of Ribovirin, Cytarabine, 5-FluorouridineOsato et al. (2003)SLC6A2NET1NoradrenalineSNP (0.07%) causes reduced affinity for NorRunkel et al. (2000)Paczkowski et al. (2002)SLC22A2OCT2ProcainamideCimetidineMetformin,QuinidineFour SNPs reduce renal eliminationLeabman et al. (2002)SLCO1B1OATP1B1Pravastatin17b-estradiol-17b-D-glucuronideSNP markedly reduces non-renal clearanceIwai et al. (2004)SLC18A2VMAT2Reserpine (inhibitor of amine uptake)Two rare SNPs alter reserpine inhibitionBurman et al. (2004)
20POLYMORPHISM OF TRANSPORTER FUNCTION GENETRANSPORTERDRUGSEFFECTS OF SINGLE NUCLEOTIDE POLYMORPHISMSREF.SLCO1B3OATP1B3Digoxin17b-estradiol-17b-D-glucuronideTaurocholateBile acid transport abolished by 2 SNPs.Letschert et al. (2004)SLC6A4SERT5-HTHaplotype associated with Bipolar Affective Disorder (Taiwan)Sun et al. (2004)SLC22A1OCT1MPP+SNPs alter substrate specificity of OCT1Kerb et al. (2002)ABCB1MDR1CyclosporineTacrolimus(calcineurin inhibitors)2677TT genotype associated with reduced risk of renal dysfunctionHerbert et al. (2003)LoperamideQuinidine2677G/3435T haplotype associated with higher plasma concentrationsSkarke et al. (2003)
21PERSPECTIVESLC, SLCO, and ABC transporters play a critical role in drug pharmacokinetics, affecting absorption, hepatic uptake, hepatic export, tissue distribution, and renal and biliary elimination.A body of unstructured pharmacogenetic data is rapidly accumulating that suggests strongly that membrane transporters are subject to both genotypic and phenotypic polymorphism.
22PERSPECTIVEGenetically-determined variability in drug and hormone transporter function may explain major inter-patient variability in drug pharmacokinetics and susceptibility to drug resistance and toxicity.These differences may be greater than those due to the known enzyme polymorphisms.There is much to do.